8/14/2019 US Food and Drug Administration: rpt0093 http://slidepdf.com/reader/full/us-food-and-drug-administration-rpt0093 1/30 Date: From: Subject: To: DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Memorandum May 8,200l 3 “7 fj $ *,$x3 &Jr &Qf -go p3 :J3 Director, Division of Standards and Labeling Regulations, Office of Nutritibnal Products, Labeling and Dietary Supplements, HFS-820 75-Day Premarket Notification for New Dietary Ingredients Dockets Management Branch, HFA-305 New Dietary Ingredient: N- Acetyl-L-Hydroxyproline Firm: Kyowa Hakko U.S’.A., Inc. Date Received by FDA: February 9,200l 90-Day Date: May lo,2001 In accordance with the requirements of section 413(a) of the Federal Food, Drug, and Cosmetic Act, the attached 75-daypremarket notification for the aforementioned new dietary ingredient should be placed on pubic display in docket number 953-03 16 after May 10,200 1. Felicia B. Satchel1
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8/14/2019 US Food and Drug Administration: rpt0093
DEPARTMENT OF HEALTH AND HUMAN SERVICEi Public Health Service
Food and Drug Administration
Washington, DC
Neil C. Sullivan
Kyowa Hakko U.S.A., Inc.599 Lexington Avenue, Suite 4103New York, New York 10022
Dear Mr. Sullivan: \
This is in response to your letter and addendum, respectively dated January 5,200l andFebruary 7,2001, making a submission for a new dietary ingredient pursuant to 21 U.S.C.5 350b(a)(2) (section 413(a)(2) of the Federal Food, Drug, and Cosmetic Act (the Act)). Your
letter notified FDA of your intent to market the substance “N-Ace@-L-Hydroxyproline(AHYP)” as a new dietary ingredient.
You state in your submission that AHYP is “an ideal candidate for a new dietary supplement
that acts on the treatment of arthritis.” Under 21 U.S.C. 3 321(g)(l)(B), a drug is defined as
an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease. The information in your submission represents that a product containing AHYP is
intended to be used to treat arthritis and therefore, is subject to regulation as a drug under
21 U.S.C. 3 321(g)(l)(B) and not as a dietary supplement. See 21 CFR 8 101.93(g). If youwish AHYP to be evaluated for its use in the treatment of arthritis, you should contact FDA’s
Center for Drug Evaluation and Research (CDER), Office of Compliance, HFD-3 lo,7520Standish Place, Rockville, Maryland 20855.
21 U.S.C. 5 35Ob(a)(2) requires that a manufacturer or distributor of a dietary supplement that
contains a new dietary ingredient submit to FDA, at least 75 days before the dietary ingredientis introduced or delivered for introduction into interstate commerce, information that is thebasis on which the manufacturer or distributor has concluded that a dietary supplementcontaining such new dietary ingredient will reasonably be expected to be safe. FDA reviews
this information to determine whether it provides an adequate basis for such a conclusion.Under 21 U.S.C $ 350b(a)(2), there must be a history of use or other evidence of safety
establishing that the dietary ingredient, when used under the conditions recommended orsuggested in the labeling of the dietary supplement, will reasonably be expected to be safe. If
this requirement is not met, the dietary supplement is deemed to be adulterated under
21 U.S.C. 3 342(f)(l)(B) because there is inadequate information to provide reasonableassurance that the new dietary ingredient does not present a significant or unreasonable risk of
illness or injury.
As we have stated above, your product containing AHYP is subject to regulation as a drug.Nonetheless, we have carefully considered the information in your submiss ion concerningwhether a dietary supplement containing AHYP will reasonably be expected to be safe if it
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were able to be marketed as a dietary supplement. We have significant concerns about theevidence on which you rely to support your conclusion that a dietary supplement containing
AHYP will reasonably be expected to be safe. Your submission indicates that use of AHYPmay result in adverse effects. You state that adverse effects include, among other things,
gastrointestinal complaints (e.g., nausea and diarrhea), allergic reactions, arthralgia, vasculitisurticaria, and allergic eosinophilia. In a search of the scientific literature, we found a clinicaltrial that reported that 25 out of 132 (18%) arthritic patients treated with 1200 mg/day AHYP(a dose within your recommended intake) experienced adverse effects, with eight patientswithdrawing from the study as a result of these effects.’ The reported effects included
gastrointestinal pain, nausea, vomiting, constipation, palpitations, dizziness, and skin rash.Although you recognize that potentially serious side effects are expected to occur with the use
of AHYP, your submiss ion contains no explanation or data that explain why these potentiallyserious side effects are not grounds for concluding that AHYP is not safe. Further, the
scientific studies you cite do not provide an adequate basis for a conclus ion that the dietarysupplement will reasonably be expected to be safe. The studies you submitted were not
designed nor intended to examine the adverse or toxicologica l effects of AHYP in healthypeople; rather, the studies mostly appear to be designed to evaluate its short-term effect inpersons suffering from serious diseases. Such efficacy studies have limited utility for
determining whether the long-term use of a substance as an ingredient in dietary supplementsis safe for healthy people.
AHYP is an anti-inflammatory agent, displaying antiphlogistic and analgesic pharmacological
properties. However, your submiss ion does not address the potential serious risks that mightexist for persons already taking drugs or other products with similar pharmacological effects,
if any, that would result from the use of products containing AHYP at your recommendedintake.
For the reasons discussed above, the information in your submission does not provide an
adequate basis to conclude that AHYP; when used under the. ecommended or suggestedconditions of use in the labeling of a dietary supplement, will reasonably be expected to be
safe. Because the information in your submission ind icates that your product is a drug and
not a dietary supplement, not only would your product be subject to regulation as a drug ifmarketed, but, even insofar as it might be argued that your product is a dietary supplement, a
dietary supplement containing AHYP would be deemed adulterated and subject to regulatoryaction pursuant to 21 U.S.C. 342(f){ l)(B) (section 402(f)(l)(B) of the Act). Further,introduction of a product containing AHYP into interstate commerce is prohibited under21 U.S.C. 6 33 (v). Therefore, a dietary supplement containing AHYP would be deemed
’ Herrmann G; Steeger D; Klasser M; Wirbitzky J; Furst M, Venbrocks R, Rohde H,Jungmichel D; Hildebrandt HD; Parnham MJ; Gimbel W; Dirschedl H (2000). Oxaceprol is awell-tolerated therapy for osteoarthritis with efficacy equivalent to diclofenac. ClinRheumatol. 19:99-104.
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adulterated and subject to regulatory action pursuant to 2 1 U.S.C. 5 33 l(v). In any event, youare not prohibited from submitting a new premarket notification for AHYP under 21 U.S.C.
350b(a)(2), if you deem such resubmiss ion appropriate.
Should you have any questions concerning this matter, please contact us at(202) 205-4168.
Sincerely yours,
Felicia B. Satchel1.
Director
Division of Standardsand Labeling Regulations
Office of Nutritional Products, Labelingand Dietary Supplements
Center for Food Safety
and Applied Nutrition
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DEPARTMENT Ol? HEALTH & HUMAN SERVICES Public Health Service
Food and Drug AdministrationWashington, dC 20204
d
Mr. Neil Sullivan3766 y gyj~ fq”l3
Manager
Kyowa Hakko U.S.A., Inc.599 Lexington Avenue, Suite 4 103
New York, New York 10022
Dear Mr. Sullivan:
This is to inform you that the notification and addendum, respectively dated January 5,200land February 7,2001, you submitted pursuant to 21 U.S.C. 350b(a)(2) were filed by the Food
and Drug Administration (FDA) on February 9,200 1. Your notification concerns the
substance called “N-Acetyl-L-Hydroxyproline (AHYP)” that you assert is a new dietary
ingredient.
In accordance with 21 C.F.R § 190.6(c), FDA must acknowledge its receipt of a notification
for a new dietary ingredient. For 75 days after the filing date (i.e., after April 25,2001), youmust not introduce or deliver for introduction into interstate commerce any dietary
supplement that contains “N-Acetyl-L-Hydroxyproline (AHYP).”
Please note that acceptance of this notification for filing is a procedural matter and thus, doesnot constitute a finding by FDA that the new dietary ingredient or supplement that contains
the new dietary ingredient is safe or is not adulterated under 21 U.S.C. 342. As anotherprocedural matter, your notification will be kept confidential for 90 days after the filing date.
After May 10,200 1, the notification will be placed on public display at FDA’s DocketManagement Branch in docket number 95S-03 16. However, any information that is trade
secret or otherwise confidential commercial information in the notification will not bedisclosed to the public. 1
Please contact us at (202) 205-4168, if you have any questions concerning this matter.
Sincerely yours,
Consumer Safety Officer
Dietary Supplements TeamDivision of Standards
and Labeling RegulationsOffice of Nutritional Products, Labeling
and Dietary SupplementsCenter for Food Safety
and Applied Nutrition
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RE: Amended S”ubmissionof New Dietary Ingredient Notification
for N-Acetyl-L-Hydroxyproline
To whom it may concern:
1. As per my recent telephone conversation with Peggy Carlson, Head of Dietary
Supplement Team we are instructed to omit the references that need an English translation.
Therefore, please omit the following numbered references:
,F>,d &Y References No.‘s ls 2,4,5,6,27 concerning the mechanisms of action of AHYP
Reference No. 10 concerning’the effect of AHYP on burn tissue
Reference No. 11 concerning the effect of AHYP on’nicotine toxicity
Reference No. 16 concerning different subject
Referenc,e No. 17 general notes on OA treatmentReference No. 18 A small scale clinical study
Reference No.‘s $9,207 21,22 Human OA clinical trials of Oxaceprol (non-English
with a summary in English)
Reference No.‘s 23,28 A brief review of the efficacy of Oxaceprol in humans
Reference No. 26 RA clinical study1, Reference No.‘s Z&,33* 35 Dermatological use of AHYP in humans
References No. 34, AHYP is not mentioned
Reference No.‘s 32,36,37 AHYP on ulcer, nikotine, cicatrization, respectively
2. For your further knowledge about AHYP, here enclosed is a product description by the
German pharmaceutical company Chephasaar. The product is trade named AHP 200Oxaceprol.The original German product information or fact sheet is attached with the
English translation. The fact sheet is informative because it describes the toxicologicalI, properties and the efficacy of AHYP.
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Composition of the drugGroup of substanc’esor indicationsAntirheumatic agent
Comoositlon
Medicallv effective comnonentsOne film-coated tablet contains200 mg of Oxaceprol-
Other comoonents
Talcum, magnesium stearate, potato starch,,Makrogoie,polymethacryfate, Povidon,propylene glycol, Simethicon,colours E 171, E 104, E 110.
Fields of applicationDegenerative joint diseases n painful or inflammatory phases, amrosese. g. of the knee, thehip, the shoulder, he spinal column, the smalljoints; polyarthroses; chondropathypatelfae, arthritis, penarthritis,bursitis, tendinitis, tendovaginitis.
Inflammatory connective issue diseases.
Contra-indicationsA known hypersensitivity o Oxaceprolor one of the other components.
Ahh&gh up to now there are no indications that Oxaceprol may havepossible teratogenic effects, t is recommended not to use AliP 20069during a pregnancy.
Side effectsUnder the treatment with Oxaceproloccasionally there have beenobserved: gastrointestinalcomplaints,such as nausea, impairedappetite, pain in the stomachor diarrhea, which are often of a passingnature. Seldom there may occur allergic reactions (a reddening of theskin, an itching of the skin, exanthemae); n exceptional cases thefollowing reactions of altergicgene&here described: loss of hair,arthralgia, vasctiltiis, urticaria,giant urticqia, allergic eosinophilia
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In’teractions With other agents ,,In patients under anticoagulativeheiapy w& 6ffmin K-antagonists(e.g. Marcumar@) an affectionof coagulation by Oxaceprolcannot beexcluded. A cfosemeshedcontrol of the prothrombin ime undersimultaneous therapy with API-J 00@ s, therefore, recommended,
Warning noticesDoesnY apply.
Most important i&ompatibilitiesNot known up to now.
DosageAs far as not dffferentfy prescribed, he standard dosage is 3 x daily 1film-coated tablet. Dependingon the severity of the affection, speciallyat the beginning of the treatment he’ daily dose can be increased o3 x 2 film-coated tablets.
Method and period of applicationAHP200@ film-coated tablets re preferably taken before a meal,unchewed, with sufficient iquid.
The period of time fbr which he drug is to be administered~depends nthe character and intensityof the affection and is to be’fixe$f ndividualfy.
Emergency procedures, symptoms and antidotesintoxications in huma,ns ave not occurred up to now and &-e actuallyhardly imaginable. In oral administr$fon during bio-assays4 nly abovethe 500- to IOOO-fold uantityof the standard dosage usual in thehuman field (IO mg/kg of bodyweight) toxical effects coufd~ e
observed (sedation, ptosis,’pifoerection).Pharmacologikal and toxicological prop&ties,pharmacokinetics 1Pharmacolouical orooertiesOxaceprof shows a distinctantiphlogistic nd analgesic efficacy.
In preclinicaf studies the arttiphlogistfcefficacy has been test&dwith anexcellent result in various models (canageenine paw edema,anaphyiactic, oint test, carrageenirie-inducedpleurisy, adjuvant-arthritis)and in comparison to referenceantfphlogistics (indometacin,ASA,phenyfbutazone, ibuprofen).These data have also been confitied with
a pyrexal erythema in the human model.
The analgesic efficacy has been shown by the Randall-Selittoand thePhenyfchinone-Writhing-test.
CfinicaIfy Oxaceprol has been ested in various indication ields ofdegenerative joint diseases. n pfacebo-controlledstudies as well as
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double-blind and randomisedstudies agaiist ibulj&fen and diclof&actQe substance has been applied ’n he therapy of gon-, cox- andspondyl-arthrosis. While the cross-over est tiersus placebo showed thesignificant superiority of Oxaceprol, he substance is equal to ibuprofenand didofenac in its symptomaticeKcacy.
In the therapy of rheumatoidarthritis Oxaceprol shows a tendency ofsuperiority to diciofenac.
In all indication fields the typical pain parameters (e.g. pain whenstarting to move, rest pain and pain following exercise), but alsoinflamtiation and flexibility parameters were d istinctly mproved.
Toxicolouical orooertiesAcute toxicityWhen orally administered, he LDSOn rats Is 7.451 mgkg of bodyweight, in mice 5.588 mg/kg of body weight; when lM-applied n rats andmice, respectively, it was more than 4,000 mg/kg a’nd2,921 mg/kg ofbody weight, respectively,
The toxicity after repeat+! administrationwas determined n rats andbeagles. For this purpose, he animals rveregiven on 29 and 28 (resp.)suc+ss’we days 3 dosagesof the agent (4.5: 36; 288 mg/kg of bodyweight). l,n rats, apart from local effects caused by the application
l
(inflammatory processes at thd injection site) no unwanted effectsoccurred. In dogs, with the two lower dosages, no effects occurred. .Wtih the highest dosage, slight changes on cornea and renal tubuleswere observed, the pathqlogical mportance of which is not known. Nocases of death occurred.
Mutagenicity
Oxaceprol was extensively ested with regard to mutagenic properties,No indications of any mutagenicpotential were found.
CefcinogenicityThere don’t exist any t&son carcinogenicity; from bio-assays andclinical tests there didnY esult any indications of a tumorigenic potential.
ReproductionIn rabbits, with the highestdosage of 288 mglkg of body weight,teratorgenic effects were observed -which, however, were notreproducible in a second, denticallyconducted study, There don’t existany data on the placentar ransport&on of Oxadeproi n humans nor
data on the transition into mother’s milk.Pharmacokinetic propertiesabsorption3.5 hours after oral applicationof Oxaceprol there are maximalplasma levels. The bio-availability fter oral administration amounts toabout 30%.
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Due to is aqueous sblubilii, Oxaceprol s distributed n the wholeorganism. It permeates nto the sinovial fiqui<. No plasma-proteinbondhas been proved. There are no iii&cations of a cumulation.
EliminationAfter IM or IV application ne elimination half-time amounts o anaverage of 2 hours. The eliminationoccurs exclusively by renalThe excretion is unchangedand complete. Oxaceprol s neither
way.
incorporated nor metabolised.
Other Endicatiorxi ’Doesn’t apply.
Indications on stabilitvAHP 200@ film-coated kblets have a shelf life o f 3expiration date the drug may not be used any more.
years.After the
Indications on storagenone
a) Indication on waste disposalUnused rests o f the drug need not be taken to a separatewastedispostil.
Presentation and package sizes100 film-coated tziblets N3)300 film-coated tablets
State of informationMarch 1999
.._
Name or company and address of the pharmaceutical businessProducerlpharm. business:GhephasaarChem--pharm. FabrikGmbHMtlhlstrasse 50D-66386 St. lngberttel.: (0 68 94) 9?1 - 0fax: (0 68 94) 971 - 199
Co-distributor;Rosen Pharma GmbHD-66377 St. lngbert
Distri butocMIP Pharrna GmbHD-66386 St. lngbert
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599 Lexington Avenue, Suite 4103New York, NY 10022,
00
Telephone: 212 319-5353 ‘Q$&p
facsimile: 212 421-1283 KYWA
January 5 ,200l /
Office of Special Nutri~onals /JXFS-800-820
Center for Food Safety and Applied Nutrition
Food and Drug Administration
200 C Street SW
Washington, DC 20204
FKE:New Dietary Ingredient Notification
To whom it may concern:
,’
As specified in the Code Of Federal Regulations, Chapter 2 1 CFR, Part 190-Dietary Supplements; Subpart B, Paragraph 190.6 for Requirement for Premarket
Notification we are submitting information about Kyowa Hakko Kogyo Co. Ltd.‘s
ingredient product N-Acetyl-L-Hydroxyproline.
Our intention‘with this notification is, o exhibit to the addressee that N-Acetyl-L-
Hydroxyproline (AHYP), an ingredient, is reasonably expected to be safe. Following
the format of the CFR notification requirements for paragraph (a), we supply answers for
the requested details as follows.
(1) Name and address of manufacturer: Kyowa Hakko Kogyo Co., Ltd.
Bio Chemicals Company(a unit of Kyowa Hal&o Kogyo Co., Ltd.
1-6-1 Ohtemachi
Chiyoda-ku, Tokyo 100-8 185
Japan
Manufacturing site: Kyowa Hal&o Kogyo Co., Ltd.
2548 Fujimagari Ube-Shi
Yamaguchi-Ken
Japan 755-8501
(2) The name of the new dietary ingredient is N-Acetyl-L-Hydroxyproline.
(3) A description of the dietary supplement. Not applicable.(i) The level of the new dietary ingredient within a supplement will be in the
range of 50 mg to 200 mg per tablet or capsule.
(ii) The conditions of use can be taken daily via oral administration with daily
intake of 100 mg to 900 mg,mwithsingle oral doses taken three to eight times
per day.
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This booklet describes an overview about N-Acetyl-L-hydroxyproline (AHYP) to help
understand why this compound is thought to be an ideal candidate for a new dietary
supplement that acts on the treatment of arthritis.
AHYP has been used widely in France and Germany as a drug named “Oxaceprol” for
the treatment of osteoarthritis, a degenerative joint disease, for over twenty years. The
preferential effects of AHYP have been confirmed in various studies on humans-and
experimental animals. Though the mechanisms of action of AHYP aie not well
understood, recent research suggests that the inhibition of neutrophil leukocyte infiltration
into the synovial membrane and periarticular soft tissue is involved.
Orally administered AHYP is readily absorbed by the body and gradually secreted into
urine and feces without being metabolized. Through the extensive clinical experience with
AHYP, its potential side effect is found mild and only seen in rare cases.r
2. ABBREVIATIONS
AHYPOFN-Acetyl-L-hydroxypro1in.e
3. EXPECTED MA~ZKETOF AHYP / MANUFACTURINGOF AHYP BY KYOWA ’
In the market of dietary supplement, the combined formula of glucosamine sulfate and
chondroitin sulfate is quite popular as the one targeting those suffering from, arthritis.Since the effectiveness and the safety of AHYP has been proved at pre-clinical and
” clinical stages, AHYP is expected to be one of the highly potential compound or formula in;‘:
nutraceut$als market.
‘8, Kyowa Hakko Kogyo Co., Ltd. has established- a patented, unique technology by which
hydroxyproline is produced by a carefully controlled fermentation with purified low-‘,‘I
molecular weight natural compounds as reaction substrates, followed by chemical
,,; modification to yield AHYP (AHYP-KYOWA). In contrast to other comm,ercially available
8’ hydroxyprolines, all of which are ,made from extracted collagen from cow or porcine origin,
AHYP-KYOWA is completely free from possible pathogenic contaminants such as viruses
and prions. We are currently expanding the production scale of our standardized AHYP-ii
KYOWA to the industrial scale supply it into the huge market of nutraceuticals worldwide.“,Ij
I
;Py,/_i’
31
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Therefore, over 50%’ of the ingested AHYP is thought to be readily moved into the bloodstream and ‘completely excreted from the body within a couple of days without being
metabolized. ” _
SAFETY DATA
Pharmaceutical preparation of AHYP, Oxaceprol, is formulated as tablets or capsules,
each contains 200mg of AHYP. Patients are recommended to take a tablet or a capsule 3
times a day. Unlike most anti-inflammatory drugs such as NSAlDs that are widely used for
the treatment of arthritis, .AHYP do not have considerable side effects at the prescribed
dosages. The extensive clinical experience’ of AHYP proved its safety on the long-term
therapy. ”., /
The product descriptioh issued by Chephasaar Chem-pharm Fabric GmbH describes the
following information about the pharmacological and toxicological properties of AHP200
(Oxaceprol). The original texts are written in German,
Pharmacoloaicai properties ’
Gxaceprolshows-a distinct antiphlogistic and analgesic efficacy.
In preclinical studies the antiphlogistic efficacy has been tested with an excellent result in
various models. (carrageenine paw’ edem-a, anaphylactic joint test, carrageenine-induced ’
pleurisy, adjuvant-arthritis) and in ‘comparison to’ reference antiphlogis tics (indomethacin;
ASA, phenylbutazone, ibuprofen). These data have also been confirmed with a pyrexal
erythema in the human model.
The analgesic efficacy has been shown by the Randall-Selitto and the
4
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Clinically Oxaceproi has been tested in various ind ication fields of degenerative joint
diseases. In placebo-controlted studies as well as double-blind and randomized studies
against ibuprofen and diclofenac the substance has been applied in the therapy of gon-,
cox- and spondyl-arthrosis. While the cross-over test versus placebo showed the
significant superiority of Oiaceprol, the substance in equal to ‘ibuprofen and diclofenac in
its symptomatic efficacy.
In the therapy of rheumatoid arthritis Oxaceprol shows a tendency of superiority to
diclofenac.
In all indication fields the typical pa in parameters {e.g. pain when starting to move, rest
pain and pain foollowing exercise), but atso inflammation and flexibility parameters were
distinctly improved.
Toxicological properties
Acute toxicity
When orally administered, the LDSOn rats is 7,751 mg/kg of body weight, in mice 5,688
mg/kg of body weight; when IM-applied in rats and mice, respectively, it was more than
4,000 mg/&g ‘and ‘2921 mg/kg of body weight respectively. . /
Chronic foxicify
.
The toxicity after repeated administration was determined in rats and beagles. For this
purpose, the animals were given on 29 and 28 (resp.) successive days 3 dosages of theagent (4.5; 36; 288 mg/kg of body weight). In rats, apart from local effects caused by the
application (inflammatory processes at the injection site) no unwanted effects ocdurred. In
dogs, with the two lower dosages, no effects occurred. With the highest dosage, slight
changes on cornea and renal tubtiles were observed, the pathological importance of ,which
is not known. No.cases of death occurred.
Mufa~enkify ,
Oxaceprol was extensively tested with regard to mutagenic properties. No indications of
any mutagenic potential were found. I
CarcinogenicitycThere don’t exist any tests on carcinogenic ity; from bio-assays and clinical tests there
didn’t result any indications of a tumorigetiic potential.
Reproduction
In rabbits, with the highest dosage of 288 mg/kg of body weight, teratogenic effects were
observed - which, however, were not reproducible in a second, identically
5
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the Joint Cartilage In vitro and ‘In vivo.Z.Rhellmatol.46(3), 136( 1987)4
l In cultured jo.int cartilage tissue of hens, AHYP (lO~g/ml) stimulated the uptake of 3H-
glucosamine and 3H-proline in chondrocytes and enhanced the incorporation of 3H-
proline into the macromolecular structures of the cartilage matrix. After in vivo intra-
articular injection of AHYP into the knee joints , a significant increase of intracellular
glucosamine uptake was observed.
/5. Effects of Various Antirheumatic Agents on the activity of collagenases.
Pharm. Unserer Zeif,20(3), 118 (1 991)5 /
l AHYP did not inhibit collagenase activity.
b. Effect of Nonsteroidal anti-inflammatory drugs on the activity of Elastase andCathepsin G from human polymorphonuclear leukocyt&. Arzneim.Forsch,39(10),1208
(1 989)6i
l AHYP (10”M to 1O”M) did not inhibit elastase and cathepsin G from human
T
polymorphonuclear leukocytes.
b. 5”
6. EFFECTS OF AHYP IN ANIMAL EXPERIMENTS
ISome pateits have been filed fqr ‘the anti-inflammat’ory and wound-healing activity of
AHYP (Bit. Pat.1246141 (1971), P.Coirre.;U.S.Pat.3891’765(1975) and 3932638(1976),,
! Franc0 Chimie)‘./
‘.II
‘; I . Effects of Oxaceprol on the microcirculation in ischemiaheperfusion injury. European‘:: , Journal of Medical Research 3(4): 182-8, (1998)*::i
l In the microcirculation of striated skin muscle of Syrian golden hamster, 45min!I,”continuous infusion of AHYP’ (50mg/k) resulted in a significant decrease in:IIpostischemic leukocyte adherence after 0.5h and 2h of reperfusion. The histological
,I1, sections revealed a significant reduction in the number of extravasated leukocytes.‘,, /I:
/:i, 2. Pharmacokinetics and metabolism of “C-Oxaceprol in beagle dogs after intramusculars
and oral administration.Anneii~~e/-forschung,4O.2OO-6,(l990)gI ;I ,’
1 , 0 Pharmacokinetics of AHYP as stated in 4. PHARMACOLOGY AND SAFETY DATA ON AHYP):’
1
3. N-Acetyl-Hydroxyproline effect on the development of experimental intermediary burns
I’.:’ in rabbits. Revue Europeenne d Etudes Cliniques et Biologiques. 17(6):625- 9.(1972)”II,/~/ ! 7 .,!I’ j.
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l Rabbits with necrotic burns of the flank were fed, during the period of scarring, 20 or
IOOng doses of AHYP mixed in the diet. The inflammatory changes and skin healing
were not altered by this treatment. However, the scar reduction in the initially burnt
zonewas less although the quantity of collagen in the scar was increased.
I4. Prevention w ith WAcetyl-hydroxyproline on the toxic cellular effects of nicotine.
Comptes Rendus des Seances de la Societe de Biologic Bt de Ses FiIiales. 65(7):1549-
54 (I 971)”
l AHYP (0.2-0.4mg/ml) prevented cellular toxicity of nicotine on KB cells and rat
embryonic fibroblasts in culture.
5. Oxaceprol, an atypical inhibitor of inflammation ,and joint damage. Pharmaco/.Res.,
33(6): 367-73 .(I 996)12/ Oxacepro l, an atypical inhibito r of inflammation and joint damage.
Z.Rheumatol., 55(1):58(1996)‘3/ Oxacepro l, an atypical inhibitor of inflammation and joint
damage..Z.Rheumato/., 55(1):118(~996)‘4
l AHYP had no effect on ‘macrophage prostaglandin E, release in vitro and inhibited
carrageenan paw oedema at 18-150 mg/kg p.o.. AHYP (654mg/kg/day p.o.) given
therapeutically had no effect on the primary paw oedema response, but inhibited‘*
secondary lesions in the ears and tail.. ,Histologically, AHYP markedly inhibited
I inflammatory cell infiltration and bone damage in the adjuvant-injected paw.‘ .
6. Effects of N-Acetyl Hydroxyproline (Oxaceprol) on an Experimental Post-Contusive,,: Model of Osteoarthritis. A pathological study. J.Drug Dev.,3(3),135-42 (1990)15
: l Orally administered’ AHYP (25mg/kg/day for three months) was effective in an‘i, 1 experimental post-contusive model of osteoarthrit,is in rabbits which was’produced by a
’ ,’blow to the patella with an iron weight of 1kg dropped twice through a cykndric guide 11%,
‘Imeter in length.
,I
:‘I, 7. EFFECTS OF AHYP IN HUMAN STUDIESI,!
The preferential clinical effect of AHYP on osteoarthritis’and rheumatoid arthritis has been:~ reported as in. he following references. _:s.I,I
l Clinical studies of use in degenerative joint disease : RSchubotz, L.Hausmann,
Therapiewoche 27, 4248 (1977)”
8
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l The conservative treatment of Gonarthrosis with Oxaceprol. Therapiewoche,
36(2),116(1986)‘9
32 patients with gonarthro+ of different degrees had been treated for 6 weeks with
Oxaceprol only. The pain at rest was controlled after a 3 weeks therapy and the circle of
the joint reduced during 3 weeks on an average of 0.7 cm and was diminished for
further 3 weeks of therapy. ‘Restricted mobility of the joint improved. Only 36% of
patients had slightly pain when staring after the 6 weeks treatment and the pain-free
walking-time increased by a factor 5. The therapy was in 80% successful. The tolerance
was good and side effects had not been noted.
0 Therapy of Coxarthrosis and Gonarthrosis with Oxaceprol. Therapiewoche, 36 (29),
3076 (1986) 2o
A total of 50 patients suffering from osteoarthritis of the hip and knee joints received
Oxaceprol at a dose ,of ZOOmg,,3 times daily fur a duration of a 8 months. Treatment
with Oxaceprol led to pronounced d iminution of pain and reduction of intake of
analgesics . Improvement was also noted in’ the course of treatment with regard to
morning stiffness, seventy and duration of pain and joint function. The tolerance was
good. No adverse reactions had been observed.
l
Therapy of chondropathia patellae with Oxaceprol. Therapiewoche, 35(28), 3388(1985) 21
:/367 patients with chondropathia patellae of different degrees have been treated for 8
weeks w ith Oxaceprol. During the therapy ‘parameters like pain and mobility were
significantfy improved. In 93.2% of all cases it was poss ible to restrict the drug treatment
I .exclusively to Oxaceprol. There were no serious adverse reactions under the Oxaceprol
therapy, only in a few cases light gastrointestinal disturbances were noticed.
i
l Therapy of Gonarthrosis with Oxaceprol. Therapiewoche, 35(l), 51 (I 985) 22
509 patients with gonarthrosis of ,different degrees have been treated for up to 8 weekswith Oxaceprol. During the therapy parameters like pain and mobility were significantly
improved. The consumption of nonsteroidal anti-rheumatic drugs was strongly reduced.
In 75.1 of all cases it was possib le, to restrict the drug treatment exclusive ly to
Oxaceprol.
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l Interaction of Fluindone with Oxaceprol. Therapiewoqhe,45(2), 162(-l 990) 27 _
l Treatment of rheumatoid arthritis. Comparative study of Oxaceprol versus diclofenac.
Therapiewoche, 46 (30), 1666-69 (I 996) 28
0 Antirheumatic agents and leukocyte recruitment. Biochemical Pharmacology, 58, 209-
215(1999) 29
,’ Some preferential effects of AHYP on diseases other than arthritis have also been
reported e.g. in the following papers.
l Clinical studies of use in treatment of burns, tumors and other wounds: Y.Privat, Gaz.
Med. de France 84, 618 (I 977)31,iI t 0 Action of ALAcetyl-hydroxyproline in the treatment of cutaneous ulcerative lesions.ml1 Annali Italiani di Chirurgia. 51(5), 527 (1979) 35
.’ : 0 Prevention of certain acute and chronic effects of nicotine. by N-1;” ,,!I1 Acetylhydroxyproline.U@Pafhologie Sio/og[e. 19(g), 497 (1971) 3681Ii1 1 0 Study of a physiologic regulator of cicatrization (N-Acetyl-hydroxyproline). Apropos of
1. Riera H et al.: Effect of Oxaceprol on the structure of proteoglycans synthesized by‘I
articular chondorocytes from calves. Revue du Rheumatisme et des Maladies Osteo-
Articulaires, B(9), 629-34 (1991)
I 2. Riera H et al.: Effect of Oxaceprol on the synthesis and degradation in vitro of
proteoglycans and’ proteins by calf at-titular cartilage exp lants. Revue du Rheumatisme
et des Maladies Osteo-Articulaires, 57(7-8$, 579-83 (1990)
3 *Steinmeyer J et al.: The inhibitory effects of antirheumatic drugs on the activity of
human leukocyte elastase and cathepsin G. Inflammation Research. 45(7), 324 (1996)
4 . Kalbhen A et al.: Autoradiographic Investigation of the influence of Oxaceprol on the
metabolism of the Joint Cartilage In vitro and In vivo.Z.Rheumatol. 46(3), 136 (1987)
5. Shug S et al.: Effects of Various Antirheumatic Agents on the activity of collagenases.
Pharm. Lkserer Zeit, 20(3), 118 (1991)~
b . Steinmeyer J et al.: Effect of Nonsteroidal Anti-Inflammatory drugs on the activity of!Elastase and Cathepsin G from human polymorphonuclear leukocytes. ArzneimForsch,
3CJ(lO), 1208 (1989)
7 -Anti-inflammatoryO@ and wound-healing activity in animals (Brit. Pat.1246141 (1971)
P.Coirre.,U.S.Pat.3891765 (1975) and 3932638 (1976), Franc0 Chimie)
8. Harris A et al.: Effects of Oxaceprol on the microcirculation in ischemia/reperfusion
injury. European Journal of Medical Research 3(4), 182-8 (1998)
9. Lachmann G et al .: Pharmacokinetics and metabolism of “C-Oxaceprol in beagle dogs
I after intramuscular and oral administration. Anneimittel-Forschung, 40, 200-6 (1990)
LO . Molimard R et al .: N-Acetyl-Hydroxyproline effect on the development of experimental
intermediary burns in rabbits. Revue Europeenne d Etudes C liniques et Biologiques.
a(6), 625-9 (1972)
11. Chany E et al .: Prevention with N-Acetyl-hydroxyproline on the toxic cellular effects of
nicotine. Comptes Rendus des Seances de la Societe de Siologie et de Ses Filiales.
65(7), 1549-54 (1971)
L2 .lonac M et al .: Oxaceprol, an atypical inhibitor of inflammation, and joint damage.PharmacoLRes., 3J(6), 367-73 (1996) . .
L3 .lonac M et al .: Oxaceprol, an atypical inhibitor of inflammation and joint damage.
Z.Rheumatcl., 55(l), 58 (1996)~
lonac M et al .: Oxaceprot, .an atypical inhibitor of inflammation and joint damage.
I,
iI 11I
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I5. Mazieres B et al.: Effects ‘of N-Acetyl l-lydroxyproline(Oxaceprol) on an Experimental5. Mazieres B et al.: Effects ‘of N-Acetyl l-lydroxyproline(Oxaceprol) on an Experimental
Post-Contusive Model of Osteoarthritis. A pathological study. J.Drug Dev., 3(3), 135-42ost-Contusive Model of Osteoarthritis. A pathological study. J.Drug Dev., 3(3), 135-42
(1990)1990)
1 b . Kalbhen A et al.: Pharmacological assessment of possibilities for chondroprotectiveb . Kalbhen A et al.: Pharmacological assessment of possibilities for chondroprotective
therapy in degenerative joint diseases(Arthroses). ZXheumafolo. 42(4), 187-l 94 (1983)herapy in degenerative joint diseases(Arthroses). ZXheumafolo. 42(4), 187-l 94 (1983)
L 7. Kalbhen A et al.: Chondroprotective treatment in arthrosis. What can it do and what is7. Kalbhen A et al.: Chondroprotective treatment in arthrosis. What can it do and what is
‘18 .Schubotz R et al.: Clinical studies of use in degenerative joint disease :,18 .Schubotz R et al.: Clinical studies of use in degenerative joint disease :,
L4 .Finkbeiner G et al.: The conservative treatment of Gonarthrosis with Gxaceprol.4 .Finkbeiner G et al.: The conservative treatment of Gonarthrosis with Gxaceprol.
20 .Michael J et al.: Therapy of Coxarthrosis and Gonarthrosis with Oxaceprol.0 .Michael J et al.: Therapy of Coxarthrosis and Gonarthrosis with Oxaceprol.
2L. Diehl K et al.: Therapy of chondropathia patellae with Oxaceprol. Therapiewoche,L. Diehl K et al.: Therapy o f chondropathia patellae with Oxacepro l. Therapiewoche,
2$. Diehl K et al.: Therapy of Gonarthrosis with Oxaceprol. Therapiewoche, 35(l), 51$. Diehl K et al.: Therapy of Gonarthrosis with Oxaceprol. Therapiewoche, 35(l), 51
~,,,,,,jtt
(I 985)I 985),ililItt 27 .Villani P et al,: Assessment of the placebo effect of symptomatic slow-acting drugs7 .Villani P et al,: Assessment of the placebo effect of symptomatic slow-acting drugs
4;/_/_
given for osteoarthritis. bresse Med. k(5), 21 I-l 4 (1998)iven for osteoarthritis. bresse Med. k(5), 21 I-l 4 (1998)
,’ i:’ i: ’8ii
24 - Juvin E et al:: A pragm atic trial of Oxaceprol 200mg in the long-term treatment of4 - Juvin E et al:: A pragm atic trial of Oxaceprol 200mg in the long-term treatment of
Il.l.25. Grellat P et al.: Clinical studies of use in several rheumatic conditions:, Rheumatologie5. Grellat P et al.: Clinical studies of use in several rheumatic conditions:, Rheumatologie
,I)/’I)/’i/l’/l’
27,223 (1975)7,223 (1975)
lj/,jj/,j26. Laborie G et al.: The acetyl-hydroxyproline,metabolic harmonization of connective6. Laborie G et al.: The acetyl-hydroxyproline,metabolic harmonization of connective
111 27. Bannwarth B et al.: Interaction of Fluindone with Oxacepro l. Theiapiewoche, 45(2),7. Bannwarth B et al.: Interaction of Fluindone with Oxacepro l. Theiapiewoche, 45(2),( IIIttI/’/’
162 (1990)62 (1990)
I/!/!I//~1:.1:.
28 . Menge M et al.: Treatment of rheumatoid arthritis. Comparative study of Oxaceprol8 . Menge M et al.: Treatment of rheumatoid arthritis. Comparative study of Oxaceprol